Transplantation-associated arteriosclerosis (TxAA) is an intimal fibroproliferative lesion composed predominantly of vascular smooth muscle cells and associated matrix proteins, admixed with mononuclear inflammatory cells. TxAA causes progressive, insidious vascular occlusion and results in allograft ischemia; it represents the major long-term limitation to solid organ transplantation. Although TxAA is largely ascribed to an immune- mediated allogeneic response, it occurs even in the setting of immunosuppression adequate to block acute parenchymal rejection, and does not correlate strictly with episodes or severity of allograft rejection. Thus, cytokine-induced endothelial dysfunction, recruitment and activation of antigen-non-specific cells, or antibody-mediated processes may modulate the development of TxAA. We have proposed that TxAA is due to a chronic delayed-type hypersensitivity response of host T cells to donor vascular wall cells, distinct from the cytolytic response characteristic of acute rejection. This chronic response persists in part because of incomplete elimination of relevant foreign antigens. Moreover, the initial immune-specific response triggers the release of antigen non-specific effectors such as macrophages and cytokine networks less susceptible to immune modulation. We propose here to continue our long-term objectives of unraveling the mechanisms by which specific effector cell subsets and cytokines initiate and promote TxAA. Using a murine heterotopic cardiac transplant model, Specific Aims of this proposal are: 1) Test the hypothesis that acute rejection and TxAA are mediated via distinct T cell subsets and cytokines. Mice genetically-deficient in particular cytokines or their receptors ("knock-outs"), as well as adoptive transfer methodology, will be used to evaluate the contribution of specific cell subsets (e.g., T-helper 1-type cells, B cells) and cytokines in either promoting or ameliorating acute rejection and TxAA. 2) Identify the mechanisms underlying our seminal observations that acute parenchymal rejection and allograft failure are accelerated in inteferon (GKO) recipients, while TxAA is completely abrogated in long-term allografts in GKO recipients. The observations point to distinct mechanisms mediating acute vs. chronic allograft pathologies, and suggest that different therapeutic interventions will be uniquely applicable to each.